DNA damage repair defect unifies theories of aging

A novel form of progeria shows aging has both DNA damage and genetic components

By Jeffrey M. Perkel | December 20, 2006

Analysis of a novel form of progeria caused by a mutation in a DNA repair gene has unified two competing theories of aging, according to a report in Nature. DNA damage induces aging, but at a rate that is genetically determined, Jan Hoeijmakers, head of the department of genetics at Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues determined after studying a patient with the disease as well as a knockout mouse model.
The novel disease, which the authors called XFE progeroid syndrome, presented as a blend of progeria, or premature aging, and symptoms more typically seen in DNA damage repair-related diseases like xeroderma pigmentosum (XP) or Cockayne syndrome. The 15-year-old patient studied showed delayed growth and problems with kidney and liver function, as well as features normally associated with aging, like hypertension. But he also displayed the increased sun sensitivity that is the hallmark of a DNA repair defect.
In the knockout mouse model of the disease, the researchers found a transcriptome profile at the age of 15 days that was similar to that of normally aged mice at 2.5 years of age, with a shift toward DNA repair and cell maintenance functions and away from growth activities. Aging can thus be viewed as a gradual shift, in the face of unrepaired DNA damage or other cellular stress, from a cellular emphasis on growth to an emphasis on staying alive, they concluded. In progeria patients, this shift occurs early in life, while in normal individuals it occurs much later.
The study arose from the unexpected finding that mutation of the DNA repair gene ERCC1, which is implicated in nucleotide excision repair of DNA, induced symptoms associated with old age in mice. "If you knock out other genes required for nucleotide excision repair to model the human disease xeroderma pigmentosum, you don't get accelerated aging, you get a cancer predisposition, so ERCC1 was a big surprise," said lead author Laura Niedernhofer, assistant professor of molecular genetics and biochemistry at the University of Pittsburgh School of Medicine.
That surprise led the team to look for human patients with a similar disease. A 15-year-old Afghan boy was referred to the Erasmus clinic genetics service because of severe and chronic sunburn, suggestive of XP, but showed progeroid symptoms as well. Genetic analysis of DNA repair pathway components in cells from this patient indicated a mutation in XPF, a gene normally associated with mild XP.
XPF, in complex with ERCC1, is involved in nucleotide excision repair of both intrastrand and interstrand DNA lesions. XP patients normally are deficient in intrastrand repair, but this patient's cells were also deficient in repairing interstrand crosslinks, which disrupt DNA replication and transcription processes. The inability to remove these more severe lesions could be an important factor in the premature aging symptoms seen in both the patient and ERCC1 mice, according to Hoeijmakers.
In particular, genes in the so-called somatotroph axis, which Niedernhofer calls "a fancy word for growth hormone and IGF1 signaling," were downregulated. The somatotroph axis governs whether cells focus on growth or maintenance functions; mutations in this axis can extend the life of model organisms, while caloric restriction, which also extends life, downregulates it.
"If the system is very high [and] insulin levels are high, you grow rapidly. If that system is tuned down, then you don't grow that abundantly, but you invest more in maintenance and repair. We call this a 'survival response,'" Hoeijmakers said.
Frederick Alt, a Howard Hughes Medical Institute Investigator and professor of genetics at Children's Hospital, Boston, who did not participate in the study, told The Scientist that the research "provides probably some of the best support to date that accumulation of unrepaired DNA damage can contribute to normal aging." Also exciting, he said, is the paper's support for a connection between DNA damage and the IGF1/insulin signaling pathway in aging.
According to Alt, who earlier this year described a different knockout mouse that also suggested a link between DNA damage, insulin signaling and aging, the key unanswered question is how the DNA repair and IGF1/insulin pathways communicate.
Leslie Gordon, medical director of the Progeria Research Foundation, praised the new study as "carefully constructed" and told The Scientist in an email that she thinks it "supports the body of evidence that shows that aging likely has many contributing elements, but perhaps feeding in to only a few common pathways downstream."
Jeffrey M. Perkel
jperkel@the-scientist.com
Links within this article:
I. Oransky, "Progeria effort pays off," The Scientist, April 1, 2006.
http://www.the-scientist.com/article/display/23290/
L.J. Niedernhofer et al., "A new progeroid syndrome reveals that genotoxic stress suppresses the somatotroph axis," Nature, 444:1038 - 43, 21/28 December 2006.
http://www.nature.com
Jan Hoeijmakers
http://www.biomedicalgenetics.nl/Members/Hoeijmakers/hoeijmakers.html
Laura Niedernhofer
http://www.mgb.pitt.edu/personnel/view.asp?uid=niedernh
Frederick Alt
http://www.hms.harvard.edu/dms/bbs/fac/alt.html
"Hot Paper: DNA Repair," The Scientist, Jan. 6, 1997
http://www.the-scientist.com/article/display/17343
R. Mostoslavsky et al., "Genomic instability and aging-like phenotype in the absence of mammalian SIRT6," Cell, 124:315 - 29, 2006.
http://dx.doi.org/10.1016/j.cell.2005.11.04
The Progeria Research Foundation
http://www.progeriaresearch.org/
S. Jay Olshansky et al. "The Longevity Dividend," The Scientist, March 1, 2006
http://www.the-scientist.com/article/display/23191

Advertisement

Comments

Aging and its causes have always been topic of discussion both at ordinary level as well as anoung scientific level. The present findings, I understad are novel and shall help reaching at concrete conclusion one day. The Science deserves appreciation for publising latest informaiton.\n\n\nDr. Arijo

It may be right to say that this study about this type of progeria caused by a mutation in a DNA repair gene may unify the two competing theories of ageing, but ageing as such is more complex a biological phenomenon. The lesions in the repair gene may seem to accelerate ageing process, but some other kind of mutations may increase the cancer predisposition, as the study underlines. The modified endocrinal signaling is another factor that has bearing on the ageing process and perhaps more important than a random genetic mutation. The two factors, DNA damage and a modified IGF1/insulin signaling pathway may contribute in conjunction for ageing, but there is more to the biology of ageing. As the news cites Leslie Gordon, ?the body of evidence that shows that ageing has many likely contributing elements, but perhaps feeding in to only a few common pathways..?\n\nFor the interested readers, I would like to add here a relevant chapter from my book, ?Ageing slowly, Living longer? ? Published in 2006. I can happily send the book in pdf format to those interested.\n\nCHAPTER EIGHT\nSECRETS TO LONGEVITY:\nTheories of Ageing\n\nTHE GENE KEY FOR \nLONGEVITY\n\nWe all do age. It is a fact of life. It was an enigma a generation back. But, now the molecular biologists experimenting with organisms such as yeast, roundworms, fruit flies, and mice have succeeded in increasing the life span by altering single genes. The altered organisms live longer and age more slowly. Further, it seems that the genetic manipulations causing these changes work through a common pathway across many species. Thus, there is an evolutionary program that controls ageing.\n\nThe worm-side story: The tiny roundworms, Caenorhabditis elegans, when exposed to environmental stress during their development, enter into a state akin to hibernation by modifying themselves into a spore like forms, called dauers. They remain in this suspended condition for long periods, till the surroundings again become hospitable to growth. This phenomenon is an indication that organisms can, as part of physiology, \n\nAgeing slowly, Living longer\n78 Secrets of Longevity:\n\nregulate their life span. This also means that genes control longevity. It was demonstrated later on that roundworms missing one copy of a gene called daf-2 during development will enter the dauer state regardless of environmental conditions. \nBy altering the single gene - called daf-2 in the DNA, scientists could double the lifespan. Daf-2 appears to be a master control gene, and by changing it, we modify the functions of many other genes in the worm's DNA. These other genes do different things: some of them make anti-oxidant proteins that protect the cells from oxidative damage; other protect the cells from getting infections by bacteria. As a consequence, there comes the dramatic effect, doubling the lifespan. \n\nThe mitochondrial genetic mutations: The genetic mutations in mitochondria, appear to trigger changes leading the cells to die and speed up the ageing process. By altering a gene called polymerase gamma, which functions as a spellchecker during the copying of mitochondrial DNA in mice led them to age fast. Around eight or nine months of age there were plenty of signs of ageing in them, such as graying of hair, \n\nAgeing slowly, Living longer\nTheories of Ageing 79\n\nloss of bone mass, loss of muscle mass, and problems in the spinal curvature.\nBecause the mitochondria also control the natural process of cell death, called apoptosis, mistakes by the spell-checking gene can cause cells to die. As mitochondrial mutations accumulate, there are increased cell deaths and appearance of the ageing characteristics. This phenomenon may be linked to ageing in humans. \nThere is some mechanisms by which the body controls mitochondrial mutations, and inhibit cell death. The studies indicate existence of a set of genes, which function to prolong life and to inhibit the effects of mitochondrial mutations. \n\nThe multiple factors: When the researchers altered daf-2 as well as reproductive hormones, the worms lived six times as long as normal and stayed young and healthy. They looked disease-resistant and did not get age-related diseases until they were much older than normal. These experiments indicate that ageing is under genetic control, rather than just a consequence of wear and tear. \nIt has been discovered that genes daf-2 and age-1 (another gene), are part of the \n\nAgeing slowly, Living longer\n80 Secrets of Longevity:\n\nsame molecular pathway. In fact, there are not many genes in the pathway that regulate ageing. The finding that daf-2 also encodes an insulin receptor, has linked ageing to another program that can extend life span in any organism ? the caloric restriction (CR).\n\nDIET AND CALORIC \nRESTRICTION \n· THE CALORIC RESTRICTION\nIn the 1930's, the researchers discovered that they could extend the life of rats by 33 percent if they put them on a very low-calorie diet. These animals lived longer, suffered fewer late-life diseases, appeared more youthful, and their biological ageing was slowed. Similar life-extending studies have been reported in other organsms, ranging from fruit flies to fish. In general, the CR regimen protects against disease and slows ageing. The animals on CR, have lower levels of circulating blood glucose, insulin, and triglycerides. But they are generally infertile.\nIn this context, limiting fat, protein or carbohydrate, without accompanying caloric reduction, does not increase the maximum lifespan. The supplementation with extra antioxidants and multivitamins also does not increase lifespan. Varying the types of fats, \n\nAgeing slowly, Living longer\nTheories of Ageing 81\n\ncarbohydrates and proteins ingested also does not have any effect. In fact, no other intervention except caloric restriction has yet been shown to slow ageing. \nIt seems probable that caloric restriction is an effective way to prolong life. The low calorie intake may work by reducing the amount of free radical produced. There are less mitochondrial mutations and less programmed cell deaths. The effects of CR on lifespan, disease, and ageing processes are applicable to virtually all species. \nBut, CR is not without certain adverse effects. There occur hunger pangs, a decreased ability to handle stresses, such as cold temperatures or infection, osteoporosis and loss of muscle mass. The caloric restriction is not easy to practise. People under 20 are advised against caloric restricted diets.\n\n· SPARSE DIETS AND LOWER \n BODY WEIGHT FOR LONGER LIFE\nReducing consumption of dietary calories is the only intervention that has been of proven value in extending the average and maximum lifespan. The data indicate that more the caloric restriction, more is the potential life extension - a pattern that holds \n\nAgeing slowly, Living longer\n82 Secrets of Longevity:\n\ngood until caloric restriction becomes actual starvation, whereupon it shortens lifespan. The adult-onset caloric restriction should be phased in gradually and accompanied by a nutrient-enriched diet. This allows appetite to adjust. \nAn optimal CR reduces the incidence of virtually all diseases of ageing such as cancer, heart disease, diabetes, osteoporosis, auto-immune disorders, neurological decline and diseases such as Alzheimer's and Parkinson's diseases. Eating less is associated with lower weight, which in turn is associated with longer life as shown by studies in centenarians. \n\n· OKINAWA EXAMPLE: \n LESS CALORIES, LONGER LIFE \nThe Japanese district of Okinawa has the longest average lifespan in the world and the highest percentage of centenarians - people living to a 100 or more. The Okinawans eat up to 40 percent fewer calories than Americans and about 20 percent fewer calories than the Japanese average. But, their diet has adequate essential ingredients. The result, the Okinawans have a reduced morta-lity and enjoy reduced morbidity from a number of diseases. \n\nAgeing slowly, Living longer\nTheories of Ageing 83\n\n· DIET, HEALTH AND LONGEVITY\n\nA diet is essentially a lifestyle choice. It may change over time because of the availability of food or with change in taste. One may alter one?s diet in the light of new knowledge. A healthy diet is generally expected to incorporate a wide variety of foods. But, there is no single best diet for everyone. There is enormous genetic variation among human beings (e.g. height, bone density, skin-fold thickness, body fat, fat-free mass, and body fat distribution). This variation is responsible for varying micro- and macro-nutrient requirements. In addition, there is a considerable variation in dietary needs at different exercise levels and at different age groups. \n\n· MECHANISM OF CR\n\nThe CR extends maximum and average life spans and improves disease resistance, including resistance to many cancers. It probably does this by a reduction in the accumulation of oxidant and free-radical damage, or because ingestion of fewer calories alter fat deposition, obesity, and hormones. There takes place an improvement in the immune response, as well. \n\nAgeing slowly, Living longer\n\n84 Secrets of Longevity:\n\n· CR IN ACTION\nThere is an issue of an immediate gratification (like taste, indulgence, luxurious eating, etc.) vs deferred substantial gains (increased lifespan, youthfulness and freedom from many diseases) later. \n\nWhen practising CR, one has to reduce everything in proportion. Thus, the calorie intake is reduced but the ratio of protein, carbohydrates, and fats is maintained on lines of a balanced diet. The basic idea is to substitute foods that have more nutrition per calorie for foods that have less nutrition per calorie, while gradually reducing the number of calories. It can be done by:\n1. Curtailing the ?whites? (bread, potatoes, pasta, and rice) ? They have poor nutrition value and a high glycemic index, resulting in excessive insulin production and insulin resistance. \n2. Curtailing the desserts and the snacks for the similar reason. Taking fruits to substitute for the desserts. Substituting drinks like juices, tea and coffee for low-calorie or empty-calorie drinks. \n3. Curtailing saturated fats: Reducing visible fat and substitute liquid oils for butter, use toned instead of full fat milk. \n\nAgeing slowly, Living longer\nTheories of Ageing 85\n\n4. Eating more vegetables of all kinds. Increasing fish consumption, especially high omega-3 oil varieties.\n\n· THE CONTROVERSIES \n ASSOCIATED WITH DIETS\nThe average diet has about 35 percent fat (12% saturated, 3% transfats, 14% monounsaturated, and 6% polyunsaturated), 50 percent carbohydrate, and 15 percent protein. The, diet advisory recommends a change from this eating pattern. \nWhereas some believe in very high carbohydrate and very low-fat diets (notably, Ornish regimen); others believe in moderately high protein and very high fat and very low carbohydrates (Atkins? regimen); still others recommend higher protein, less saturated fat, but more polyunsaturated and monounsaturated fats (Sears? regimen), and more mono and poly fats, with reduced carbohydrates (Reaven?s regimen). \n\n· DIETARY COMPOSITION \n OF MACRO-NUTRIENTS \n The modern diet may look like the recommended diet, but has more saturated fat and a bit less carbohydrates. The heart disease is related to saturated fat. The extra \n\nAgeing slowly, Living longer\n86 Secrets of Longevity:\n\nweight due to too much food can lead to development of diabetes. \nThe carbohydrates consumed in the actual modern diet are low in nutrients (potatoes, breads, etc.). They lead to ?crowding out? of vegetables and fruits. \n The consensus is that CR increases the need for protein intake, relative to non-caloric restricted diets. The protein intake should be doubled from 0.8 gm/kg of body weight/day to 1.6g/kg/day. By substantially curtailing starches and sugars, one can increase the weight of the nutritionally dense, but low-calorie vegetables and fruits. \n\n· CARBOHYDRATES \n AND THE GLYCEMIC INDEX\nThe glucose-insulin feedback loop is a feedback control. When we eat high glycemic index carbohydrates and, thus, putting more total glucose into our system, some of this glucose forms cross-links with proteins, called non-enzymatic glycosylation. These cross-links enhance ageing. In addition, the raised glucose after a meal leads to increased insulin in the bloodstream, required to enable glucose to go into the cells. More insulin helps temporarily but promotes insulin resistance and metabolic syndrome. Because \n\nAgeing slowly, Living longer\nTheories of Ageing 87\n\nof these two reasons, a low-glycemic index food is to be preferred.\nThus, fasting on certain days (getting the same number of calories by alternating days with no food with days with lots of food) or erratic intake of food during the day (missing a meal followed by a heavy meal) is likely to result in greater fluctuations of insulin, than eating more evenly. An essentially continuous nutrient flow is considered the best way to even blood glucose and minimize insulin output. Also, caloric restriction will become more difficult with practice of fasting on certain days.\n\n· THE CR AND ROLE OF EXERCISE\nThe exercise helps, both physically and mentally. There take place a number of molecular changes in the brain due to exercise. It increases the production of brain-derived neurotrophic factor (BDNF), which protects nerve cells and increases the number of nerve cells that are involved in various aspects of memory and cognition.\nThe human brain begins to shrink in volume at about age 30, and as a normal process of ageing continues to lose volume until the end of life. The aerobic exercise slows down the loss of brain tissue in older \n\nAgeing slowly, Living longer\n88 Secrets of Longevity:\n\nadults. These effects are predominantly seen in three key areas of the brain: the frontal, temporal and parietal regions. The frontal region regulates memory, planning, scheduling, decision-making, etc. The temporal region is related to memory and memory consolidation. The parietal region is related to recall and navigation. \nIt may appear strange, but losing weight via increased caloric expenditure, i.e. exercise, does not give CR?s health benefits. The reason lies in the free radical concept. The food is the source of 90 percent of the oxidants or free radicals. Reducing food intake will reduce oxidative damage. Exercise, in fact, contributes to increased free radical generation by burning food faster. But, these negative effects are more than offset by health benefits of exercise, so the average lifespan is certainly increased by exercise. But, exercise does not add anything to the maximum lifespan and fairly little to the average lifespan when there is already a calorie restriction. \nIn the meantime, researchers are looking for metabolic pathways for drug targets that might prolong human life. The insulin-signaling pathway seems especially \n\nAgeing slowly, Living longer\nTheories of Ageing 89\n\npromising. ?Holy grail? is a drug that tricks cells into thinking they have been deprived of calories. These cells might activate processes that prolong life, without the need for CR or extreme dieting.\n\n\nROS AND METABOLIC \nDYSFUNCTION\n· ROS AND ANTIOXIDANTS: \nThe free radical theory of ageing is fundamental to the understanding of ageing. We can look at the uncontrolled metabolic dysfunction as a model for accelerated ageing. For example, the obesity is a disturbed metabolic state, having potential to cause metabolic syndrome, in which insulin-resistance leads to diabetes, heart disease and other changes akin to ageing related disorders. \nThe ROS or free radicals are highly energetic molecules. They are chemically hyper-active and react with molecules including DNA and cellular proteins, oxidizing and damaging them and giving rise to mutations and other abnormalities leading them to become dysfunctional. The anti-oxidants, on the other hand, mop-up free radicals and help in reducing their \n\nAgeing slowly, Living longer\n90 Secrets of Longevity:\n\ndamaging effects. In the mice experimental studies, the antioxidant effect was obvious in increasing the longevity as well as in preventing morbidity. There was less evidence of heart disease and there occurred fewer cataracts than in normally ageing mice. \nMany human diseases are associated with ageing. By suitably using antioxidants, it is possible to delay or retard the underlying process of ageing. In the studies, taking anti-oxidant supplements like Vitamin C and E might not have helped, but eating fruits and vegetables rich in antioxidants is known to improve the health.\n· STUDIES IN YEAST:\n THE STABILIZING PROTEINS\nThe yeast is a single-celled fungus whose life span is defined by the number of times it can divide. It divides 20 times on average?40 times at most. The reorganization of DNA over the course of the cell?s lifetime is linked to its death. But when the cell?s DNA is stabilized, both the average and maximum lifespans increase. One of the proteins that stabilizes the chromosomes of a yeast cell, encoded by a gene of the same name, is called sir2. When an extra copy of Sir2 gene was introduced into a yeast cell, enabling to \n\nAgeing slowly, Living longer\nTheories of Ageing 91\n\ngenerate about twice as much sir2 protein and stabilizing the DNA, the yeast lived about 30 percent longer. Sir2 is believed to be the founding member, in evolutionary terms, of a family of genes known as sirtuins that are present in all complex life forms.\nThe Sir2 gene is activated when the yeast cells are stressed. It in turn acts to stabilize the chromosome, making the cells to live longer. More recently, another gene has been identified that controls Sir2, a master regulator called, PNC1. Stress turns on the PNC1 gene, the activity of which turns on Sir2.\nThere is a set of plant molecules (the sirtuin activating compounds, STACs), which activates the sir2 protein. On feeding these molecules to yeast cells, they live longer. These molecules act through Sir2, because when that gene is deleted, the effect is vanished. When, STACs are fed to roundworms and flies, they also live longer. It seems that the STACs may be universally efficacious, even in humans. \n· THE LINKS BETWEEN \n SIRTUINS AND CR\nThere appears to be a relationship between sirtuins, insulin-signaling pathway \n\nAgeing slowly, Living longer\n92 Secrets of Longevity:\n\nand the caloric restriction. The sirtuins are controlled by insulin and another closely related hormone, insulin-like growth factor-1 (IGF-1). In mammals, there is SIRT1 gene (equivalent to Sir2 in yeast) which rises when levels of insulin and IGF-1 fall, as they do in a calorie-restricted organism. When sirtuins are triggered by STACs they don?t cause infertility, as occurs with caloric restriction. Thus, with STACs we can get all the benefits of caloric restriction without the tradeoffs like infertility. \n· HORMESIS:\n BENEFITS OF MILD STRESS\nThe concept that mild stress might lead to health benefits is called hormesis. Plants given low doses of a herbicide, for example, can actually become stronger and grow better. It is thought that STACs increase lifespan because they are produced by plants when stressed or starving. The plants make these molecules to turn on their own protective sirtuin genes in order to defend themselves. \nResveratrol is a plant extract of 50 percent unknown composition. Studies prove resveratrol?s role in yeast longevity. But the molecule is very sensitive to light and \n\nAgeing slowly, Living longer\nTheories of Ageing 93\n\nair, and has a short shelf life. A high level of resveratrol is present in red wines. The molecule, which is concentrated in the skins of grapes, is highly insoluble in water. The red wine is made from grapes is processed with their skins, and alcohol is used for extraction. Traditionally, the wine is stored in dark, light-proof bottles, corked to keep oxygen out. The resveratrol is thus preserved in red wines.\n· METABOLISM AND \n OXIDATIVE STRESS\nThe life span has been linked to metabolic rate. The metabolism generates free radicals - reactive oxygen species (ROS) - that can damage DNA and proteins. Animals that live fast, die young; because a high metabolic rate produces large number of free radicals. According to this theory, long-lived animals should have high concentrations of antioxidant enzymes in their tissues and low concentrations of free radicals. But, this has not been proved. \n\nThere is another related theory, which states that metabolic stability is a better predictor of longevity than metabolic rate. It proposes that an organism?s ability to maintain stable levels of free radicals is more \n\nAgeing slowly, Living longer\n94 Secrets of Longevity:\n\nimportant than how fast it produces them. According to this the pharmacological agents that simply act to reduce ROS concentrations may even be harmful, because they could perturb the delicate balance necessary for normal cell function.\n\n· ACCUMULATION OF \n FREE RADICAL DAMAGE\nThe accumulation of free-radical damage may be the key regulator of life span. Thus, there may arise ability to resist free-radical damage by genetic alterations in the insulin-signaling pathway. It appears that the gene daf-2 is a potent gene that triggers multiple factors leading to increase the longevity. While some genes downstream from daf-2 encode antioxidant proteins, which protect the body against damage from free radicals, others code for protein ?chaperones,? which help proteins fold and take them to the lysosomal garbage cans when they are decomposed, and still other genes encode anti-microbial agents that kill bacteria and fungi, while a set of metabolic genes, when turned down, also promotes longevity.\nThus, the increased ability to withstand environmental insults increases longevity. The metabolic stability is more important \n\nAgeing slowly, Living longer\nTheories of Ageing 95\n\nthan metabolic rate in determining life span. In fact, ageing research has shown that long-lived animals are more resistant to pathogens and other environmental stresses.\nThe correlation between disease-resistance and longevity has led researchers to test the efficacy of sirtuins against various diseases associated with ageing, like Alzheimer?s disease and other neuro-degenerative disorders. The sirtuins appear to be pro-survival molecules. Feeding the lab mice resveratrol, a sirtuin-activating compounds derived from plants, suppresses the growth of implanted cancer tumors.\n\nRELATING THE LAB RESEARCH \nTO LONGEVITY IN HUMANS\nThe prime question is whether the interventions that work in lab animals will work in humans? Extending the life span of a fly or a worm or a yeast cell is exciting, but easy because they have just one type of receptor for both insulin and growth hormones. But, in complex animals these pathways diverge: mammals have separate insulin and insulin-like growth-factor receptors. Although these receptors in mammals are structurally and functionally \n\nAgeing slowly, Living longer\n96 Secrets of Longevity:\n\nvery similar, one is part of a system that regulates metabolism, while the other primarily mediates growth. In mammals, changes in either pathway can lead to long-lived mutants. \nThe insulin signaling has connections to diabetes and metabolic syndrome. In the experimental mouse, if insulin signaling is knocked out in fat tissue (FIRKO mouse) it remains lean as it ages. The FIRKO mouse is not more active than normal one. Even their internal body temperatures are the same. They are not excreting extra calories, so they are being burned up in excess energy utilization by some mechanism that does not involve being more active. One hypothesis is that the FIRKO mice are metabolically inefficient. The calorie-restricted animals also exhibit an altered metabolism. They are slightly less efficient at converting food into energy, but produce fewer free radicals and so experience less oxidative damage. \nThe links between insulin signaling, caloric restriction, and obesity could be centered on fat tissue. There is a possibility that fat either makes or accumulates something that is toxic. Fat is known to make hormones called adipokines, which may act \n\nAgeing slowly, Living longer\nTheories of Ageing 97\n\non other tissues to alter longevity. Alternatively, fat could be a source of molecules involved in oxidative stress, such as free radicals. \nIn human muscle, there is a decrease in oxidative metabolism with age. Given these emerging connections among diabetes, oxidative metabolism, and ageing in muscle and fat, there appears to be a common oxidative pathway that becomes less efficient with age. \n\n \nLESSONS FROM NEW ENGLAND \nCENTENARIAN PROJECT \nThe Project points that, there is a tendency toward longevity clusters in population groups. In many centenarians? families, longevity appears to be a dominant trait. Also, that one in 10,000 people alive today has longevity genes. \nWe all have the same genes, but vary from each other based on our SNPs or single nucleotide polymorphisms. The vast majority of these SNPs have no impact on longevity. But a few of them might increase the likelihood of high cholesterol, cardiovascular disease, or Alzheimer?s disease. Negative mutations can accumulate in the course of \n\nAgeing slowly, Living longer\n98 Secrets of Longevity:\n\nevolution, as long as they do not affect fertility or life span during an organism?s reproductive years. In addition to being free of the negative genetic variations common in other human beings, the centenarians also have some positive mutations that increase the possibility of longer life span.\nThe genes work differently in different populations, depending on environmental influences. A gene that leads to high blood-lipid levels in primitive, physically active, food-limited populations might promote longevity in them, but can cause heart disease and lead to early death in a sedentary modern urban. Nevertheless, the clustering of genetic variations among centenarians suggests that there may be one or two genes common among long-lived individuals that have a much stronger influence than others.\n\nUNDERSTANDING AGEING PHENOMENON:\nTHEORIES OF AGEING\n\nThere is a growing interest in the topic that why and how ageing occurs; and there is search for a general theory that can explain of phenomenon of ageing. The empirical observations on ageing have become \n\nAgeing slowly, Living longer\nTheories of Ageing 99\n\nnumerous and abundant adding to the confusion. To transform these numerous and diverse observations into a comprehensive body of knowledge, a general theory of species ageing and longevity is required. A general theory of ageing may come in the future from the synthesis between systems theory (reliability theory) and specific biological knowledge, which is based on the evolutionary theories of ageing relying on the biological evolution by natural selection.\n\nTHE RELIABILITY THEORY \nOF AGEING\nAgeing can be understood as the summary term for a set of processes, which contribute to health deterioration and ultimately to death with the passage of time. These processes contribute to the age-related decline in performance, productivity and health. Here, the failure is an outcome, according to the reliability theory, when the system deviates from optimistically anticipated and desired behavior. \nThe reliability theory predicts that a system may deteriorate with age even if it is built from non-aging elements with constant failure rate. The key issue here is the system's redundancy for irreplaceable \n\nAgeing slowly, Living longer\n100 Secrets of Longevity:\n\nelements, which is responsible for the ageing phenomenon. There may be no specific underlying elementary ageing process itself - instead ageing may be largely a property of redundant system as a whole. \n\nEXPLANATION BY\nTHE RELIABILITY THEORY\nThe reliability theory is a general theory of systems failure applied in mechanical engineering setting. This theory can allow us to predict the age-related failure kinetics for a given system and given reliability of its components. Thus:\n· Redundancy is a key notion for understanding ageing and the systemic nature of ageing in particular. Systems, which are redundant in numbers of irreplaceable elements, do deteriorate over time (i.e. age), even if they are built of non-aging elements.\n· Paradoxically, the apparent ageing rate or expression of ageing is higher for systems with higher redundancy levels. \nRedundancy exhaustion over the life course explains the observed mortality convergence at later life as well as the observed late-life mortality deceleration, leveling-off, and mortality plateaus.\n \nAgeing slowly, Living longer\nTheories of Ageing 101\n\n· Living organisms seem to be formed with a high load of initial damage, and therefore their lifespan and aging patterns may be sensitive to early-life conditions that determine this initial damage load during early development.\n· Reliability theory explains why mortality rates increase exponentially with age, by taking into account the initial flaws (defects) in newly formed systems.\n· Reliability theory helps evolutionary theories to explain how the onset of deleterious outcomes can be postponed by a simple increase in initial redundancy levels. From the reliability perspective, the increase in initial redundancy levels is the simplest way to improve survival particularly at early reproductive ages.\n\nEVOLUTIONARY THEORIES \nOF AGEING\nFollowing are the major evolutionary theories of ageing: \n· Mutation accumulation theory, \n· Antagonistic pleiotropy theory, \n· Disposable soma theory, and \n· Theory of programmed death, \nAt present the most viable evolutionary theories are the mutation accumulation \n\nAgeing slowly, Living longer\n102 Secrets of Longevity:\n\ntheory and the antagonistic pleiotropy theory. But, these theories are not mutually exclusive.\n\nBASICS OF EVOLUTIONARY THEORY\nEvolutionary theories of ageing and longevity try to explain the remarkable differences in observed ageing rates and longevity records across different biological species through interplay between the processes of mutation and selection. There are some puzzling observations of the life cycles of some biological species. For example, a bamboo plant reproduces asexually for about 100 years, forming a dense stand of plants. Then in one season all of the plants flower simultaneously, reproduce sexually, and die. A similar observation is seen in the pacific salmon. Thus, there has evolved the idea that sexual reproduction may come with a cost for species longevity. Thus, in addition to mutation and selection, the reproductive cost, or, more generally, the trade-offs between different traits of organisms may also contribute to the evolution of species ageing and longevity. The evolutionary theories of ageing are closely related to the genetics of ageing because biological evolution is \n\nAgeing slowly, Living longer\nTheories of Ageing 103\n\npossible only for heritable manifestations of ageing. \n\nThe Darwin's theory is based on the idea of random and heritable variation of biological traits between individuals (caused by mutations) with subsequent natural selection for preferential reproduction of those individuals who are particularly fit to a given environment. It is expected, therefore, that the biological evolution acts to increase the fitness and performance of species evolving in successive generations. From this perspective it is difficult to understand why natural selection leads to senescence and late-life degenerative diseases instead of eternal youth and immortality. In addition, many manifestations of ageing occur after the reproductive period of organisms. \nBut, the ageing and lifespan do evolve in subsequent generations of biological species in a theoretically predicted manner depending on particular living conditions. For example, a selection for later reproduction produced, as expected, longer-lived fruit flies while placing animals in a more dangerous environment with high extrinsic mortality redirected evolution, as predicted, to a shorter lifespan in subsequent generations. \n\nAgeing slowly, Living longer\n104 Secrets of Longevity:\n\nThus, the evolutionary theory is consistent with the plasticity of ageing and longevity.\n\nTHE EVOLUTIONARY THEORIES IN ACTION\nThe evolutionary theory of ageing may be considered as part of a more general life history theory, which tries to explain how evolution designs organisms to achieve reproductive success and avoid extinction. It answers why some organisms are small or large, why do they mature early or late, why do they have few or many offspring, why do they have a short or a long life, and why must they grow old and die. \nCurrent evolutionary explanations of ageing and limited longevity of biological species are based on following major evolutionary theories: \n· Mutation accumulation theory: From the evolutionary perspective, ageing is an inevitable result of the declining force of natural selection with age. Over successive generations, late-acting deleterious mutations will accumulate, leading to an increase in mortality rates late in life. This evolutionary theory, considers ageing a byproduct of natural selection. \nAccording to this theory, persons loaded \n\nAgeing slowly, Living longer\nTheories of Ageing 105\n\nwith a deleterious mutation have fewer chances to reproduce if the deleterious effect of this mutation is expressed earlier in life. By contrast, people expressing a mutation at older ages can reproduce before the illness occurs, such as the case with familial Alzheimer's disease. This prediction was tested through the analysis of genealogical data on familial longevity in European royal and noble families, data well known for their reliability and accuracy. It was found that the regression slope for the dependence of offspring lifespan on parental lifespan increases with parental lifespan, exactly as predicted by the mutation accumulation theory. \n\n· Antagonistic pleiotropy theory: Late-acting deleterious genes may even be favored by selection and be actively accumulated in populations if they have any beneficial effects early in life. \n\nAn example of antagonistic pleiotropy refers to replicative cellular senescence (cell division limit), which is known to suppress tumorigenesis by switching cells into a state of arrested growth. This very process that suppresses tumorigenesis early in life, however, may promote cancer in later life \n\n\nAgeing slowly, Living longer\n\n\n106 Secrets of Longevity:\n\nbecause senescent cells stimulate other premalignant and malignant cells to proliferate and to form tumors. Here again there is a trade-off between the earlier protective effect of growth arrest because of \ncellular senescence and the later detrimental effect caused by cancer promotion. \nThe antagonistic pleiotropy theory also explains why reproduction may come with a cost for species longevity and may even induce death, as in bamboo plants and pacific salmon. Indeed, any mutations favoring more intensive reproduction (more offspring produced) will be propagated in future generations even if these mutations have some deleterious effects in later life. For example, mutations causing overproduction of sex hormones may increase the sex drive, libido, reproductive efforts, and success, and therefore they may be favored by selection despite causing prostate cancer (in males) and ovarian cancer (in females) later in life. Thus, the idea of reproductive cost, or more generally of trade-offs, between different traits of the \n\nAgeing slowly, Living longer\nTheories of Ageing 107\n\norganism follows directly from antagonistic pleiotropy theory. \nThese predictions were tested. By postponing reproduction to later ages, the intensity of selection on the later stages of life was increased. This selection for late reproduction increased lifespan of the selected populations. Interestingly, the \nincrease in longevity was accompanied by an evolutionary decline in fertility early in adult life, confirming the prediction of the antagonistic pleiotropy theory. \nMost researchers agree that the disposable soma theory is a special, more narrowly defined variant of the antagonistic pleiotropy theory of aging. The antagonistic pleiotropy theory is also known as the ?pay later? theory. \n\nThese two theories of ageing, namelymutation accumulation theory and antagonistic pleiotropy theory are not mutually exclusive. In fact, both evolutio-nary mechanisms may operate at the same time. The main difference between the two theories is that in the mutation accumulation theory, genes with negative effects at old age accumulate passively from \none generation to the next while in the \n\nAgeing slowly, Living longer\n\n108 Secrets of Longevity:\n\nantagonistic pleiotropy theory, these genes are actively kept in the gene pool by selection.\n\n· Weismann?s Theory of Programmed Death: It states that there exists a specific \ndeath-mechanism designed by natural selection to eliminate the old, and therefore worn-out, members of a population. The purpose of this programmed death of the old is to clean up the living space and to free up resources for younger generations. This theory is no longer taken seriously.\nSuggesting the theory of programmed death, Weismann came to an idea that there is a specific limitation on the number of divisions that somatic cells might undergo. The cell division limit was initially challenged. Many researchers know now that the concept of cell division limit, which became known as the Hayflick limit, was ultimately confirmed. \n\nTHE PREDICTATORS \nOF LONGEVITY\nThere is an unusual pattern of human lifespan inheritance. It has been discovered that there is no lifespan heritability, if parental lifespan is below a threshold age of \n\nAgeing slowly, Living longer\n\n\nTheories of Ageing 109\n\n75-85 years and there is a strong heritability\nof human lifespan if parents live longer lives. \nIt has also been found that the early circumstances of human life, such as the month of birth, may have a profound effect 30 years later on the chances of survival. These finding indicates that there may have been critical periods early in human \ndevelopment that are particularly sensitive to seasonal variations in living conditions, such as seasonal vitamin deficiencies or seasonal exposure to pathogens, etc. \nThe studies also show that paternal age at person's conception may be an important predictor of lifespan. This may be related to the mutation load or other genetic damage in paternal sperm cells playing a significant role in determining the human lifespan.\n\nIMPLICATIONS OF \nTHEORIES OF AGEING\nThe theories of ageing are useful because they open new opportunities for research by suggesting testable predictions. In fact, the field of ageing research has been completely transformed in the past decades. \n\nAgeing slowly, Living longer\n110 Secrets of Longevity:\n\nWhen single genes are changed, animals that should be old stay young. Numerous studies demonstrate that many manifestations of ageing can be postponed or even reversed, and that lifespan can be significantly extended in experimental animals. The studies have found remarkable plasticity of ageing and longevity and a significant potential for further extension of human lifespan.\n\nOn this basis we begin to think of ageing as a disease that can be cured, or at least postponed. Research in the field of ageing holds unlimited promises of slowing ageing and increasing longevity along with better health. \n\n\nDr. Vinod Nikhra, New Delhi, India\nEmail: drvinodnikhra@rediffmail.com\n\n\n\n\n